AIDS 2006; Toronto, Canada; August 13-18, 2006

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The Body PRO Covers: The XVI International AIDS Conference

Zidovudine/Lamivudine Inferior as First-Line NRTI Backbone

August 15, 2006

Most antiretroviral guidelines suggest that the nucleoside reverse transcriptase inhibitor (NRTI) backbone for antiretroviral-naive individuals should consist of zidovudine/lamivudine (AZT/3TC, Combivir), tenofovir/emtricitabine (TDF/FTC, Truvada), or tenofovir (TDF, Viread) + lamivudine (3TC, Epivir). The British HIV Association guidelines also suggest fixed-dose abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) as an alternate first-choice backbone.1 A recent study comparing two of these backbones -- tenofovir/emtricitabine and zidovudine/lamivudine -- suggests that zidovudine/lamivudine should no longer be selected as the first-line backbone for treatment-naive individuals when other agents are available.2

Study 934 is a large, industry-sponsored, open-label, phase 3 trial comparing tenofovir/emtricitabine + efavirenz (EFV, Sustiva, Stocrin) versus zidovudine/lamivudine + efavirenz in antiretroviral-naive individuals that is planned to continue for 144 weeks. The long-term nature of this study will allow the durability of the regimens and the long-term toxicity of the backbones to be examined. The 48-week results of the study were previously announced in a press release issued by Gilead Sciences, Inc., in February 2005.3 The preliminary findings showed higher rates of virological suppression to levels below 400 copies/mL and 50 copies/mL for patients assigned to the tenofovir/emtricitabine + efavirenz arm. More recent results through 96 weeks of treatment were presented at the XVI International AIDS Conference by Joel Gallant and colleagues.2

A total of 255 patients were randomized to the tenofovir/emtricitabine + efavirenz arm, and 254 were randomized to the zidovudine/lamivudine + efavirenz arm. The baseline demographics of the patients were similar between the two arms. The mean CD4+ cell count was 233 cells/mm3 and 241 cells/mm3 for patients in the tenofovir/emtricitabine and zidovudine/lamivudine arms, respectively, with 42% and 41% having CD4+ cell counts below 200 cells/mm3. The median HIV-1 RNA level was 5.0 log10 copies/mL in both arms.

After excluding patients with baseline non-nucleoside reverse transcriptase inhibitor mutations, 75% of tenofovir/emtricitabine + efavirenz patients and 62% of zidovudine/lamivudine + efavirenz patients had viral loads below 400 copies/mL at 96 weeks according to the time-to-loss-of-virologic-response algorithm, which was significant at a level of P = .004.

Proportion with HIV-RNA < 400 c/mL (TLOVR) (n = 463)

However, the significant difference between the two arms was lost when an HIV-1 RNA threshold below 50 copies/mL was applied. Although a higher proportion of individuals in the tenofovir/emtricitabine arm reached this level of viral suppression, the proportion of zidovudine/lamivudine patients achieving this threshold was comparable (67% versus 61%). The mean absolute increase in CD4+ cell count was also significantly greater in the tenofovir/emtricitabine arm versus the zidovudine/lamivudine arm (270 cells/mm3 versus 237 cells/mm3; P = .036).

The differences between the two arms were explained by higher rates of cessation due to adverse events in the zidovudine/lamivudine + efavirenz arm (12% versus 5% for the tenofovir/emtricitabine + efavirenz arm), which principally consisted of anemia and virologic rebound (5% versus less than 1%).

Genotypic resistance tests were performed for 14 patients on tenofovir/emtricitabine + efavirenz and 29 patients on zidovudine/lamivudine + efavirenz who experienced virologic failure (HIV-1 RNA greater than 400 copies/mL) while on treatment. No patients developed the K65R mutation associated with resistance to tenofovir. The likelihood of developing the M184V/I mutation was 50% less for patients receiving the tenofovir/emtricitabine backbone. This has been seen in other cross-comparisons of emtricitabine- and lamivudine-containing regimens.

GenotypeTDF/FTC + EFV
(n = 14), n
(n = 29), n
Wild type47
Any resistance1020
Efavirenz resistance1018

As already mentioned, anemia, a recognized side effect of zidovudine (AZT, Retrovir), was more frequently observed among patients receiving the zidovudine/lamivudine backbone (14 versus 0 patients on tenofovir/emtricitabine; P < .001). There were no other significant differences in toxicities between the two arms that led to discontinuation of treatment.

A major concern with tenofovir-containing regimens is the possible development of renal dysfunction. No individual receiving tenofovir/emtricitabine + efavirenz experienced serum creatinine toxicity -- even grade 1 events -- although there was a significant reduction in the glomerular filtration rate when measured by the Modification of Diet in Renal Disease equation, but not the Cockcroft-Gault equation. Whereas total limb fat remained stable in the tenofovir/emtricitabine + efavirenz arm, the value was abnormally low in the zidovudine/lamivudine + efavirenz arm at 48 weeks (6.0 kg) and decreased further by 96 weeks (5.5 kg).

Median (Q1, Q3) Total Limb Fat

Study 934 provides critical information for helping clinicians select the optimal NRTI backbone for individuals commencing antiretroviral therapy.

The improvement in virological outcome in patients receiving tenofovir/emtricitabine + efavirenz was maintained throughout 96 weeks, thus showing that the responses previously reported at 48 weeks are durable. It is important to note that the durable virologic outcomes were driven not only by less virological failure in the tenofovir/emtricitabine + efavirenz arm, but also by less toxicity than that experienced by patients in the zidovudine/lamivudine + efavirenz arm. In individuals who did experience virologic failure, the development of resistance was less common with the tenofovir/emtricitabine backbone, particularly development of the M184V/I mutation.

In addition to improved virologic outcomes, the tenofovir/emtricitabine backbone was associated with little toxicity. In this study, no patient developed even grade 1 abnormal creatinine levels. However, the potential for reduction of glomerular filtration rates suggests that clinicians should continue to screen for renal abnormalities and perform long-term follow-up in patients receiving tenofovir. No results were presented for bone mineral density or lipid changes, although at 48 weeks, favorable changes in cholesterol levels were observed among patients on tenofovir/emtricitabine + efavirenz.

Lipodystrophy is a significant concern with antiretroviral treatment and is clearly associated with the use of thymidine analogs. Findings from Study 934 add to the data that zidovudine, in addition to stavudine (d4T, Zerit), is associated with this toxicity.

So what do these findings mean for the treating clinician? Certainly, there seems to be no reason to continue to use zidovudine/lamivudine as the preferred NRTI backbone in treatment-naive patients; tenofovir/emtricitabine seems to be a more effective and less toxic combination. Moreover, tenofovir/emtricitabine can be dosed once daily and in a combined tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV, Atripla) tablet. Pharmacokinetic data presented at the meeting showed that the triple-drug tablet has an identical pharmacokinetic profile to those of the individual agents.4

Mean (95% CI) Plasma Concentration-Time Profiles of FDC Versus Individual Drugs
Click to enlarge

In addition, the data on the possible development of lipodystrophy with zidovudine/lamivudine-containing regimens and the stability in limb fat observed with the tenofovir/emtricitabine backbone suggest that individuals on zidovudine/lamivudine with virologically controlled HIV should consider switching to a regimen containing a non-thymidine analog, either tenofovir or abacavir (ABC, Ziagen).


  1. BHIVA Writing Committee on behalf of the BHIVA Executive Committee. BHIVA Guidelines for the Treatment of HIV-Infected Adults With Antiretroviral Therapy 2005. British HIV Association; 2005. Available at: Accessed August 15, 2006.

  2. Gallant J, Pozniak A, DeJesus E, et al, and the Study 934 Team. Efficacy and safety of tenofovir DF (TDF), emtricitabine (FTC) and efavirenz (EFV) compared to fixed dose zidovudine/lamivudine (CBV) and EFV through 96 weeks in antiretroviral treatment-naive patients. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0064.
    View poster: Download PDF

  3. Gilead announces preliminary 48-week data from Study 934 comparing Viread and Emtriva to Combivir both in combination with Sustiva in patients with HIV [press release]. Gilead Sciences, Inc.; February 3, 2005. Available at: Accessed August 15, 2006.

  4. Mathias A, Plummer A, Skillington J, et al. Bioequivalence of the co-formulation of efavirenz/emtricitabine/tenofovir DF. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0098.
    View poster: Download PDF

It is a part of the publication XVI International AIDS Conference.

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